Type 2 diabetes mellitus is one of the most prevalent metabolic diseases that is characterized by hyperinsulinemia, insulin resistance, and defect(s) in islet secretory function. Pancreatic ?-cells dynamically respond to fluctuations in blood glucose with the regulated secretion of insulin. Increased understanding of the molecular signaling mechanisms that underlie the function of these dynamic, insulin-producing cells will aid in the development of more effective therapies. TCPTP is a ubiquitously expressed non-receptor protein-tyrosine phosphatase. Mice with whole-body TCPTP deletion exhibit hematopoietic defects and die after birth thus hampering detailed assessment of their metabolic phenotype. The function of TCPTP in the pancreas remains largely unresolved, but a growing body of evidence suggests a role in ?-cell function. Genome-wide association screens identified PTPN2 as a susceptibility gene involved in the pathogenesis of type 1 diabetes. In addition, TCPTP regulates cytokine-induced ?-cell apoptosis. Moreover, TCPTP modulates endoplasmic reticulum stress signaling in the glucose-responsive MIN6 ?-cells. Further, TCPTP is a key regulator of insulin, leptin, and c-Src signaling pathways which play important roles in ?-cell function. To determine the physiological role of TCPTP in pancreatic islets, we will employ two complementary approaches. We will generate pancreas TCPTP knockout (KO) mice to study the direct consequences of TCPTP loss in the pancreas in vivo. In addition, we will determine the effects of TCPTP knockdown and pharmacological inhibition on ?-cell function. Equally important is the dissection of the molecular mechanisms mediating TCPTP actions. In preliminary studies we demonstrated that: (i) pancreas TCPTP KO mice exhibited impaired glucose tolerance and attenuated glucose-stimulated insulin secretion (GSIS). (ii) The secretory defect in GSIS was confirmed in ex vivo studies indicating that the effects were cell autonomous. (iii) TCPTP knockdown and pharmacological inhibition in MIN6 ?-cells attenuated GSIS. (iv) Identified STAT3 as a TCPTP substrate in ?-cells. The broad goals of this proposal are to investigate the physiological role of TCPTP in pancreas endocrine function with the long-term aim of generating therapies for the treatment of diabetes.